Cancer is one of the main diseases threatening human life. Surgery, radiotherapy and chemotherapy are currently the main means of cancer treatment. Drugs which are able to penetrate into tumors and kill tumor cells with less damage to normal cells are ideal for chemotherapy. However, most traditional chemotherapeutic drugs lack the selectivity in killing cells. With the in-depth understanding of the molecular mechanism of tumorigenesis and tumor progression, and the discovery of tumor markers, drugs for targeting therapies have become a new trend in the development of tumor chemotherapeutic drugs (Nero T L et al. Nat Rev Cancer. 2014, 14: 248-62; Goel H L et al. Nat Rev Cancer. 2013, 13: 871-82).
A tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily. The full-length molecule consists of 281 amino acids, including the N-terminal hydrophobic transmembrane domain and the C-terminal hydrophilic extracellular domain. TRAIL has four membrane-bound receptors (TRAIL R1, R2, R3 and R4) and a soluble receptor (OPG). Of these receptors, only TRAIL R1 and R2 are death receptors (DRs). Once bound to TRAIL, the DRs on the cell membrane could be activated followed by induction of apoptosis. However, TRAIL R3 and R4 receptors are both decoy receptors (DcRs), which do not trigger apoptosis upon ligand engagement. The death receptors TRAIL R1 and R2 are overexpressed in tumor cells, whereas the decoy receptors R3 and R4 are overexpressed in normal cells. Thus, TRAIL can induce tumor apoptosis, sparing normal cells (Gonzalvez F et al. Oncogene. 2010, 29: 4752-65). Both in vitro and in vivo studies demonstrate that human soluble TRAIL produced by genetic engineering displays potent killing effects cytotoxicity in breast cancer, colon cancer, lung cancer, prostate cancer, kidney cancer, bladder cancer, liver cancer, osteosarcoma, chondroma, lymphoma, neuroblastoma, hematological tumors (Stucke D W et al. Trends Mol Med. 2013, 19(11): 685-94; Wilson N S et al. Cancer Cell. 2012, 22(1): 80-90). Human soluble TRAIL has entered clinical trial phase I-II as an anti-tumor drug. It was found that TRAIL was well tolerated, and patients with a variety of tumors showed response to the treatment of TRAIL suggesting that TRAIL might be developed as a novel anti-cancer drug (Subbiah V et al. Mol Cancer Ther. 2012, 11(11): 2541-6. Soria J C et al. J Clin Oncol. 2011, 29(33): 4442-51).
However, the clinical anti-tumor efficacy of this format of soluble TRAIL is still unsatisfactory, mainly due to the wide distribution of its decoy receptors and poor targeting for tumors. The tumor-targeting of TRAIL might be enhanced by fusing TRAIL to antibodies or tumor-homing peptides that can specifically bind tumor cells, so as to further improve the anti-tumor effects of TRAIL in vivo.
The F3 peptide consists of amino acids 17-48 of a human high mobility group nucleosomal binding protein 2, which is capable of specifically binding to tumor cells and tumor vascular endothelial cells (Porkka K et al. Proc. Natl. Acad. Sci. USA. 2002, 99 (11): 7444-9), and enhancing the targeting properties of certain anti-tumor drugs. However, the F3 peptide has not been reported to be used to enhance the tumor-targeting of TRAIL so as to further improve its anti-tumor activity.